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    Clinical Trial Results:
    A Phase 1, Open-label, Multi-center Study of Clofarabine in Japanese Pediatric Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia

    Summary
    EudraCT number
    2015-001172-21
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    23 May 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    23 May 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLO05908
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01196013
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Sep 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety, tolerability and pharmacokinetics (PK) of clofarabine administered intravenously to pediatric subjects with relapsed or refractory acute lymphoblastic leukemia (ALL) or for whom no other therapy with greater potential clinical benefit exists. The dosing regimen for the intravenous (IV) clofarabine was 30 or 52 mg/m^2/day for 5 days.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia might have been used to minimize distress and discomfort.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 9 sites in Japan. A total of 7 subjects were enrolled between 18 August 2010 and 23 May 2011.

    Pre-assignment
    Screening details
    All enrolled subjects were treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Clofarabine 30 mg/m²/day
    Arm description
    Clofarabine 30 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days). If no subject developed dose limiting toxicity (DLT), subjects received 52 mg/m²/day from Cycle 2 up to a total of 6 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    JC0707
    Other name
    Evoltra®, Clolar
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Clofarabine administered once daily over 2 hours infusion. If 2 DLTs occurred, dose was reduced to 22.5 mg/m²/day.

    Arm title
    Clofarabine 52 mg/m²/day
    Arm description
    Clofarabine 52 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days) up to a total of 6 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    JC0707
    Other name
    Evoltra®, Clolar
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Clofarabine administered once daily over 2 hours infusion. If 2 DLTs occurred, dose was reduced to 40 mg/m²/day.

    Number of subjects in period 1
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Started
    3
    4
    Completed
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clofarabine 30 mg/m²/day
    Reporting group description
    Clofarabine 30 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days). If no subject developed dose limiting toxicity (DLT), subjects received 52 mg/m²/day from Cycle 2 up to a total of 6 cycles.

    Reporting group title
    Clofarabine 52 mg/m²/day
    Reporting group description
    Clofarabine 52 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days) up to a total of 6 cycles.

    Reporting group values
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day Total
    Number of subjects
    3 4 7
    Age categorical
    Units: Subjects
        Children (2-11 years)
    3 2 5
        Adolescents (12-17 years)
    0 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    4 ± 1 12.8 ± 2.75 -
    Gender categorical
    Units: Subjects
        Female
    1 2 3
        Male
    2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Clofarabine 30 mg/m²/day
    Reporting group description
    Clofarabine 30 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days). If no subject developed dose limiting toxicity (DLT), subjects received 52 mg/m²/day from Cycle 2 up to a total of 6 cycles.

    Reporting group title
    Clofarabine 52 mg/m²/day
    Reporting group description
    Clofarabine 52 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days) up to a total of 6 cycles.

    Subject analysis set title
    Clofarabine
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects (Clofarabine 30 mg/m^2/day + Clofarabine 52 mg/m^2/day) included in the study and who received at least 1 dose of clofarabine.

    Primary: Maximum Tolerated Dose (MTD)

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    End point title
    Maximum Tolerated Dose (MTD) [1]
    End point description
    The MTD was defined as the highest dose at which < 2/6 subjects experience a DLT during the first cycle. Analysis was carried out on safety population comprised of all subjects who received at least 1 dose of the study drug. Here '99999' represents 'not applicable' as no subject experienced any DLT.
    End point type
    Primary
    End point timeframe
    Baseline up to 14 days (Cycle 1)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    Clofarabine
    Number of subjects analysed
    7
    Units: mg
        number (not applicable)
    99999
    No statistical analyses for this end point

    Primary: Maximum Drug Plasma Concentration (Cmax)

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    End point title
    Maximum Drug Plasma Concentration (Cmax) [2]
    End point description
    Analysis was carried out on pharmacokinetic (PK) analysis set which included subjects who received at least 1 dose of clofarabine and had measurable drug concentrations. 'Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Primary
    End point timeframe
    0 hour (Predose) on Day 1-5 of Cycle 1; >0 to 1, 2 (end of infusion), >2.5 to 4, >4.5 to 7, >7.5 to 10 hours after infusion; on Day 1 and Day 5 of Cycle 1
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Number of subjects analysed
    3
    4
    Units: percent of coefficient of variation
    geometric mean (geometric coefficient of variation)
        On Day 1 (n=3,4)
    221 ± 6.6
    675.4 ± 18.1
        On Day 5 (n=2,4)
    229.7 ± 35.5
    578.8 ± 30.8
    No statistical analyses for this end point

    Primary: Time to Maximum Plasma Concentration (Tmax) and Elimination Half-life (t1/2)

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    End point title
    Time to Maximum Plasma Concentration (Tmax) and Elimination Half-life (t1/2) [3]
    End point description
    Analysis was carried out on pharmacokinetic (PK) analysis set which included subjects who received at least 1 dose of clofarabine and had measurable drug concentrations. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Primary
    End point timeframe
    0 hour (Predose) on Day 1-5 of Cycle 1; >0 to 1, 2 (end of infusion), >2.5 to 4, >4.5 to 7, >7.5 to 10 hours after infusion; on Day 1 and Day 5 of Cycle 1
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Number of subjects analysed
    3
    4
    Units: percent of coefficient of variation
    geometric mean (geometric coefficient of variation)
        Tmax: On Day 1 (n=3,4)
    1.822 ± 1.1
    1.914 ± 5.8
        Tmax: On Day 5 (n=2,4)
    1.925 ± 0.6
    1.974 ± 4.4
        t1/2: On Day 1 (n=3,4)
    5.504 ± 42.1
    3.901 ± 14.6
        t1/2: On Day 5 (n=2,4)
    2.459 ± 2.3
    1.968 ± 10.9
    No statistical analyses for this end point

    Primary: Area Under the Drug-Concentration Curve (AUC)

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    End point title
    Area Under the Drug-Concentration Curve (AUC) [4]
    End point description
    Analysis was carried out on pharmacokinetic (PK) analysis set which included subjects who received at least 1 dose of clofarabine and had measurable drug concentrations. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Primary
    End point timeframe
    0 hour (Predose) on Day 1-5 of Cycle 1; >0 to 1, 2 (end of infusion), >2.5 to 4, >4.5 to 7, >7.5 to 10 hours after infusion; on Day 1 and Day 5 of Cycle 1
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Number of subjects analysed
    3
    4
    Units: percent of coefficient of variation
    geometric mean (geometric coefficient of variation)
        AUC0-24 h: On Day 1 (n=3,4)
    885.9 ± 29.2
    2325.2 ± 20
        AUC0-10 h: On Day 5 (n=2,4)
    619.1 ± 42.5
    1446.6 ± 17.4
    No statistical analyses for this end point

    Primary: Renal Clearance (CLr)

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    End point title
    Renal Clearance (CLr) [5]
    End point description
    Analysis was carried out on pharmacokinetic (PK) analysis set which included subjects who received at least 1 dose of clofarabine and had measurable drug concentrations.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0 to 6, >6 to 12, >12 to 24 hours after infusion; on Day 1 of Cycle 1
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Number of subjects analysed
    3
    4
    Units: percent of coefficient of variation
    geometric mean (geometric coefficient of variation)
        CLr
    13.16 ± 73.7
    23.69 ± 30.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Day 45) regardless of seriousness or relationship to investigational product
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that are AEs that developed/worsened during the ‘on treatment period’ (time from first infusion of study drug up to 45 days after the last infusion of study drug). Analysis was done on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Clofarabine 30 mg/m²/day
    Reporting group description
    Clofarabine 30 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days). If no subject developed DLT, subjects received 52 mg/m²/day from Cycle 2 up to a total of 6 cycles.

    Reporting group title
    Clofarabine 52 mg/m²/day
    Reporting group description
    Clofarabine 52 mg/m²/day from Day 1 to Day 5 in Cycle 1 (14 days) up to a total of 6 cycles.

    Serious adverse events
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Clofarabine 30 mg/m²/day Clofarabine 52 mg/m²/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    Investigations
    Activated Partial Thromboplastin Time Prolonged
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 4 (50.00%)
         occurrences all number
    5
    2
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 4 (50.00%)
         occurrences all number
    5
    2
    Bilirubin Conjugated Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood Bilirubin Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Platelet Count Decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Cardiac disorders
    Pericardial Effusion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Anaemia
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Febrile Neutropenia
         subjects affected / exposed
    3 / 3 (100.00%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Generalised Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Injection Site Reaction
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Oral Disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    1
    5
    Perianal Erythema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2010
    - Addition of exclusion criteria (had any other investigational agent received within 30 days prior to the first dose of the study drug). - Reprint of the description of the pharmacogenetic analysis method.
    04 Feb 2011
    - Edit of comment in exclusion criteria (In the case of a false positive of Hepatitis B surface [HBs] antibody, the subjects were eligible only if proved to be negative by for Hepatitis B Virus [HBV] Polymerase Chain Reaction [PCR] methods.) - Prolongation of study period.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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